|ÊDrug addiction investigators with joint appointments at Columbia University Medical Center and the New York State Psychiatric Institute, along with MediciNova, Inc., a biopharmaceutical company, have reported preliminary results of the companyÕs neurological drug candidate, ibudilast(MN-166/AV411), in a Phase 1b/2a trial in opioid addicts.
As there are no non-opioid drugs approved for treatment of dependence to opioids or methamphetamine, ibudilast is one of the few known new-approach treatments being investigated clinically.Ê Largely funded by the National Institute on Drug Abuse (NIDA) with MediciNova supplementation, the trial was led by Sandra Comer, PhD, Professor of Clinical Neurobiology, and colleagues, including Ziva Cooper, PhD, Assistant Professor of Clinical Neurobiology.
Preliminary data analyses by Drs. Comer and Cooper indicated that ibudilast was safe and well-tolerated in all subjects and that certain endpoints revealed ibudilast efficacy. ÒIbudilast treatment appeared to dose-dependently decrease the subjective symptoms of opioid withdrawal and appears to reverse tolerance to opioid-elicited analgesic, physiological, and subjective effects,Ó said Dr. Comer.
According to MediciNova Chief Scientific Officer Kirk Johnson, PhD, the findings come from a well-controlled trial and are Òthe first to demonstrate the potential utility of a glial modulator like ibudilast, with macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE)-inhibiting actions, for potentially treating opioid dependence and pain in humans.Ó
ÒThe positive outcome of our collaboration with Columbia/NYSPI and NIDA paired with company-sponsored trials wherein ibudilast has been safety dosed up to 100 mg/day bodes well for ongoing exploratory drug development,Ó Dr. Johnson added.
For the 21-day, inpatient, double-blind, placebo-controlled study, 30 heroin-dependent volunteers were enrolled and maintained on oral morphine for the first 14 days. In the first week, all subjects received Placebo and on Day 8, participants were randomized to continue placebo (P), low dose (L; 20 mg twice daily (40 mg/day)), or high dose (H; 40 mg twice daily (80 mg/day)) ibudilast.
Data were analyzed from 10 subjects completing each treatment arm. In the third week, morphine was no longer administered such that withdrawal phenomena during detoxification could be monitored. Primary endpoints were safety/tolerability and changes in total subjective opioid withdrawal scale (SOWS) score.
Secondary endpoints included other withdrawal scales and analgesia and physiological measurements. Indicators of altered analgesia or tolerance (reduced opioid effects with repeat morphine exposure) were assessed in laboratory sessions with oxycodone administration and cold water immersion of the hand followed by objective and subjective pain endpoints.
Ratings on the Subjective Opioid Withdrawal Scale, the trialÕs primary endpoint, were higher during the third week (days 15-21) relative to the first two weeks in the P and L groups (p less than or equal to 0.05), but not in the H group. Oxycodone-induced decreases in subjective pain ratings, a measure of analgesia, were lower during the second week relative to the first week in the H group (p less than or equal to 0.01).
Similarly, tolerance was observed to the physiological effects of oxycodone in the P group with decreased oxycodone-induced miosis during the second week relative to the first week, and increased oxycodone-induced miosis in the L and H groups during the second week (p less than or equal to 0.05).
Ibudilast has been used in asthma and post-stroke disorders in Japan for nearly 20 years and has also been utilized at higher doses with encouraging outcomes in MediciNova-sponsored clinical trials in multiple sclerosis and neuropathic pain. Collaborative trial planning between drug addiction research experts at organizations like Columbia/NYSPI and UCLA have led to NIDA-supported pre-clinical and clinical investigations for both opioid and methamphetamine addiction.